Piperazine sulfonamide BACE1 inhibitors: Design,synthesis, and in vivo characterization |
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| Authors: | Jared Cumming Suresh Babu Ying Huang Carolyn Carrol Xia Chen Leonard Favreau William Greenlee Tao Guo Matthew Kennedy Reshma Kuvelkar Thuy Le Guoqing Li Nansie McHugh Peter Orth Lynne Ozgur Eric Parker Kurt Saionz Andrew Stamford Corey Strickland Dawit Tadesse Qi Zhang |
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| Institution: | 1. Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Ligand Pharmaceuticals, Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA |
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| Abstract: | With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2′ sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Aβ40 in transgenic mice with a single subcutaneous dose. |
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